Cellular Strategies for Tolerance Induction

耐受诱导的细胞策略

• 批准号: 10609610
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 69.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609610
• 关键词: Address; Adoptive Transfer; Allografting; Antibody Therapy; Antigens; Autoimmunity; Biological Models; Bone Marrow; Cell Therapy; Chimerism; Chronic; Clinic; Clinical; Clinical Trials; Complex; Data; Development; Education; End stage renal failure; Ensure; Exposure to; Face; Goals; Health; Hematopoiesis; Hematopoietic; Immune; Immune Tolerance; Immunity; Immunosuppression; Immunosuppressive Agents; Kidney Transplantation; Lead; Life; Longevity; Macaca mulatta; Mediating; Modeling; Morbidity - disease rate; Mus; Organ Transplantation; Pathway interactions; Patient Care; Patients; Pattern; Pharmacology; Pre-Clinical Model; Preparation; Prevention; Publishing; Regimen; Regulatory T-Lymphocyte; Risk; Solid; System; T-Lymphocyte; Testing; Thymus Gland; Toxic effect; Translations; Transplant Recipients; Transplantation; Transplantation Tolerance; allograft rejection; base; central tolerance; clinical application; clinically relevant; combinatorial; design; experience; experimental study; graft vs host disease; immunomodulatory strategy; immunoregulation; improved; in vivo; isoimmunity; kidney allograft; mortality; mouse model; nonhuman primate; novel; preservation; response; success; trafficking; translational approach; translational model

Renal transplantation represents first-line therapy for patients with ESRD, with the most recent data documenting significant one-year success rates. However, patients continue to face high morbidity and mortality after transplant, both from chronic allograft rejection and from the toxicities associated with standard immunosuppressive regimens. Given these dual risks, the ultimate goal in this field is the induction of immune tolerance after transplantation, which promises life-long acceptance of an allograft, without the need for ongoing immunosuppression and importantly, with preservation of protective immunity. While novel pharmacologic and antibody-based therapies represent real promise in terms of greatly prolonging allograft survival and reducing off-target toxicities, murine studies strongly suggest that the most robust strategies for inducing immune tolerance incorporate cellular therapies, including both mixedchimerism induction (especially in combination with T cell costimulation blockade) and regulatory T cell (Treg)-based approaches. Both of these therapies hold the promise of fundamentally resetting recipient immunity in favor of allograft acceptance, and thus provide a direct pathway towards immune toleranceinduction. In this Project, we will explore the following Aims, each designed to advance the use of cellular therapies for tolerance induction after renal transplantation: Specific Aim #1: To induce immune tolerance to a renal allograft through the induction of stable, full-spectrum mixed-hematopoietic chimerism in the setting of T cell costimulation blockade. Specific Aim #2: To utilize regulatory T cells to induce stable, full-spectrum mixed-chimerism and immune tolerance during renal transplantation.

肾移植代表ESRD患者的一线治疗，并具有最新数据 记录一年的成功率。但是，患者继续面临高发病率和 移植后的死亡率，包括慢性同种异体移植排斥和与之相关的毒性 标准免疫抑制方案。考虑到这些双重风险，该领域的最终目标是 移植后诱导免疫耐受性，这有望接受同种异体移植的终身接受 不需要持续的免疫抑制，重要的是，保护性免疫。 而新颖的药理学和基于抗体的疗法在很大程度上代表了真正的希望 延长同种异体移植存活并降低脱靶毒性，鼠研究强烈表明最多 诱导免疫耐受性的鲁棒策略融合了细胞疗法，包括混合神经诱导（尤其是与T细胞共刺激阻滞结合）和调节性T细胞 （Treg）基于基于的方法。这两种疗法都有从根本上重置接受者的承诺 有利于同种异体接受的免疫力，因此为免疫耐受诱导提供了直接的途径。在这个项目中，我们将探讨以下目标，每个目标都旨在提高蜂窝的使用 肾移植后耐受性诱导的疗法：特定目的＃1：诱导免疫耐受性 通过诱导稳定的，全谱的混合杂种嵌合体的诱导肾脏同种异体移植 T细胞共刺激阻滞的设置。 特定目的＃2：利用调节性T细胞诱导稳定，全谱的混合性和免疫 肾移植期间的公差。